Among the most common causes of damage to biological tissue are oxidative processes that result in the production of free radicals. These highly reactive species frequently cause unwanted reactions which can damage biological tissues. In addition, free radicals can initiate chain reactions that result in the continued formation of new free radicals. Such chain reactions can damage many constituent molecules that comprise biological tissue before the reactions are ultimately terminated.
Free radicals can be formed by any one, or a combination, of a large number of oxidizing agents, oxidation-inducing agents and certain microbial agents including certain viruses. Examples of well-known oxidizing agents which promote the production of free radicals include the following: ozone, oxygen, halogens, hypochlorite (bleach), nitrogen oxides, hydrogen peroxide, ionizing radiation, combustion products, and ultraviolet radiation. Examples of oxidation-inducing agents include the chemotherapeutic agents doxorubicin (Adriamycin.RTM.) and bleomycin (Bleonoxane.RTM.). Examples of some viruses that appear to produce tissue damage by causing increased oxidizing activity include HIV (human immunodeficiency virus, or AIDS virus) and influenza virus. Although most oxidizing agents are naturally occurring substances, many of them are produced in large quantities from artificial sources such as internal combustion engines, cigarettes, electrical equipment, arc discharge sources, high energy lamps, water treatment procedures, and commercial manufacturing and processing operations.
The biological damage that is produced by the aforementioned oxidizing agents is primarily due to their involvement in the production of free radicals. Often, free radicals cause unwanted biological damage by creating structural damage to lipids, nucleic acids, protein, and many other biomolecules. The following are representative examples of free radical-induced biological damage.
Humans and most living organisms require some exposure to sunlight for optimum health. However, exposure to the shorter wavelength components of sunlight (ultraviolet e.g., 320 nm or shorter) can cause topical tissue damage such as erythema (sunburn), premature aging of the skin (e.g., drying, wrinkling, loss of elasticity, abnormal pigmentation), cancer and activation of viruses such as herpes as well as immune suppression. It is believed that much of the damage caused by sunlight is the result of chain reactions which originate when the ultraviolet light promotes the production within the tissue surface of free radicals such as superoxide and hydroxyl. Similar processes of free radical tissue damage are caused by exposure to other forms of energetic radiation such as radioactivity, X-rays, gamma rays and the like.
Smoking is known to be a major cause of lung cancer, emphysema, and other respiratory tract diseases, as well as cardiovascular diseases. Even non-smokers who are exposed to tobacco smoke (i.e., "second hand smoke") are at a higher risk for these disorders. Tobacco smoke, as well as byproducts of other combustion processes (e.g., internal combustion engines, heating and cooking with fuels, natural fires) are known to contain free radical species which are thought to be major contributors to tissue damage.
Several other forms of respiratory tract damage are thought to be linked to free radical oxidation. These other forms include respiratory distress syndrome, pulmonary vasoconstriction, influenza, pneumonia, asthma, damage caused by ischemia reperfusion, and damage resulting from auxiliary breathing systems or respirator therapies that involve the use of supplemental oxygen and/or increased gas pressure.
A very common result of respiratory tract damage and of virtually all forms of oxidative tissue damage is inflammation. In the respiratory tract, inflammation, whether caused by chemical agents, radiation, microbes or viruses, contributes to difficulty in breathing and to impairment of oxygen transport into the blood.
Antioxidants are chemical compounds that inhibit free radical oxidation by neutralizing free radicals. Biological systems generally contain internal mechanisms to protect against oxidative free radical damage. Organisms including humans have at least two different classes of antioxidants useful in preventing oxidative damage. One class, known as antioxidant enzymes, is normally produced by the body's own cells, and serves to neutralize various types of free radicals throughout the body. For example, superoxide dismutase (SOD) is a natural antioxidant enzyme that converts the superoxide radical into a less harmful species. Additionally, glutathione peroxidases and catalase remove excess hydrogen peroxide--a compound that is harmful to cells and can generate free radicals. A second class of antioxidants present in biological organisms includes certain nutrients. For example, vitamins E (tocopherol), C (ascorbate), and beta-carotene are all known to be antioxidants and free radical scavengers.
Additionally, phenolic antioxidants, both natural and synthetic, are commonly used to counteract and/or prevent free radical-induced oxidative damage. Butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA) are examples of synthetic antioxidants that are added to pastries, oils, and other foods to retard rancidity. Probucol, another synthetic antioxidant, is effective in animal, and humans against lipid oxidation and atherosclerosis. Vitamin E, mentioned above, is an example of a naturally occurring material used to counteract or prevent oxidative damage.
Antioxidants for human use are usually provided orally as a solid (e.g. tablet), liquid, or liquid solution. For example, beta-carotene and vitamins C and E are commonly taken as solids (tablets, capsules) or as solutions. The drug Lorelco (probucol) is typically taken as a tablet. (Physicians Desk Reference, 43rd edition, 1989, page 1415). Occasionally, an antioxidant may be administered via inhalation, in the form of an aerosol. See, for example, Z. Borok et al., "Effect of glutathione aerosol on oxidant-antioxidant imbalance in idiopathic pulmonary fibrosis" Lancet 338(8761), 215-216 (1991), and R. Buhl et al., "Augmentation of glutathione in the fluid lining of the epithelium of the lower respiratory tract by directly administering glutathione aerosol" Proceedings of the National Academy of Sciences 87(11), 4063-4067 (1990), both of which are incorporated herein by references for all purposes. Fine droplets, however, are difficult to uniformly produce and deliver to relatively inaccessible sites. For example, spray droplets delivered via inhalation tend to accumulate in the upper respiratory tract, without penetrating into the inner reaches of the lung.
Thus, it can be seen that there is a need for a penetrating, easy to deliver form of antioxidant. This type of antioxidant can have very important medical and environmental health benefits.